Galanthamine derivatives and process for their preparation

ABSTRACT

A process for preparing a compound having formula (11), comprises oxidative cyclization of a tertiary amine having formula (12), wherein X 1  is a removable functionality, X 2  is hydrogen or a group as defined above for X 1 , and R 1  is selected from hydrogen and alkyl, aryl, alkaryl and aralkyl groups having up to 20 carbon atoms, and R 2  and R 3  are independently selected from hydrogen and alkyl, aryl, alkaryl, aralkyl and acyl groups having up to 20 carbon atoms. Novel compounds are both used and produced by that process. ##STR1##

FIELD OF THE INVENTION

This invention relates to the discovery of a novel process for themanufacture of galanthamine and related compounds, in racemic or inoptically-enriched form, and to novel intermediates in that process.

BACKGROUND OF THE INVENTION

(-)-Galanthamine (and related compounds) are useful compounds for thetreatment of Alzheimer's disease and related illnesses. Currentlygalanthamine is usually obtained by extraction from particular types ofbulbs, such as daffodils or snowdrops.

It is known that single enantiomer galanthamine (2) can be prepared fromracemic narwedine (1) through resolution followed by reduction of theenone function, as depicted in Scheme 1, below. Usefully, since theenantiomers of narwedine (1) readily equilibrate (racemise) by way ofreversible ring opening to a dienone, coupled to the fact that crystalsof racemic (1) exist as a conglomerate of enantiomers, a dynamicresolution of (1) can be carried out by crystallisation with entrainmentby crystals of the desired isomer (see Barton and Kirby, J. Chem. Soc.(C) (1962) 806). However, in respect of a total synthesis, racemicnarwedine itself is not readily available.

Numerous processes have been based on the biomimetic approach pioneeredby Barton and Kirby in 1962, in which the key oxidative cyclisation stepproceeded in only 1.4% yield. In later studies it was found that theyields of the phenolic coupling could be increased substantially bydeactivation of the basic amine as either an amide or sulphonamidegroup, and by blocking the para-position with a removable group (i.e.replaceable by hydrogen) such as bromine, e.g. as in compound (3) inScheme 2 below; see for instance Franck and Lubs, Liebigs. Ann. Chem.(1968) 720: 131; Kametani et al., J. Chem. Soc., Chem. Comm. (1969) 425and J. Chem. Soc.(C) (1969) 2602-2605 and Szewczyk et al., J.Heterocyclic Chem. (1988) 1809).

However, processes operating on this strategy are cumbersome owing tothe need to remove the amine protecting group from the product of thephenolic coupling (compound (4) in Scheme 2) by reduction. Thisinvariably leads to concomitant reduction of the narwedine carbonylgroup, and possibly other functional groups, producing racemicgalanthamine and/or epigalanthamine, or derivatives thereof, as depictedby compound (5) in Scheme 2. To obtain racemic narwedine (1) from thelatter compounds then requires a separate reoxidation step.

SUMMARY OF THE INVENTION

Surprisingly, it has now been discovered that phenolic coupling of thegeneral type described above can be carried out with acceptable yieldwithout the need to render non-basic the amine functionality in thecyclisation precursor. This discovery is particularly advantageousbecause the product of the phenolic coupling does not need to undergothe cumbersome reduction-oxidation procedure to afford narwedine.

Accordingly, in one aspect of the present invention a process forpreparing an optically-enriched compound having the formula (11), below,comprises oxidative cyclisation of a tertiary amine having the formula(12), below, wherein X¹ is a removable functionality, X² is hydrogen ora removable functionality, R¹ is selected from hydrogen and alkyl, aryl,alkaryl, aralkyl groups having up to 20 carbon atoms, and R² and R³ areindependently selected from hydrogen and alkyl, aryl, alkaryl, aralkyland acyl groups having up to 20 carbon atoms. Resolution and reductionof the resulting compounds leads to optically-enriched compounds havingthe galanthamine structure as depicted by formula (10), below.

According to other aspects of the present invention, novel compoundshaving the formulae (10), (11) and (12 ) and are defined in the claims.Of particular interest are the optically-enriched forms of compounds(10) and (11), and in particular when enriched in the enantiomer whichhas the stereochemical configuration of (-)-galanthamine, whichtherefore allow ready access to (-)-galanthamine per se. Byoptically-enriched typically we mean an enantiomeric excess of at least50%, preferably at least 80%, more preferably at least 90% or higher,thereby including single enantiomer form.

DESCRIPTION OF THE INVENTION

In the above, X¹ is described as a removable functionality, which meansany group replaceable by hydrogen. Examples of suitable groups for X¹include the halogens, tert-butyl and O-E groups, wherein E comprises agroup linked by a carbon, sulphur or phosphorus atom. Preferably X¹ is ahalogen atom, and more preferably it is bromine.

As has been explained above, the key to the present invention is that R¹need not be acyl, or some other protecting group for the nitrogen atom,to achieve acceptable yield in the phenolic coupling reaction.Preferably R¹ is alkyl, preferably C₁₋₁₀ alkyl, and most preferablymethyl. For instance, a preferred cyclisation is shown in Scheme 3below, where the amine (6) is converted to bromonarwedine (7). This canthen be readily reduced, or de-brominated, to racemic narwedine by anappropriate chemoselective method, eg. using a palladium catalyst, whichcan then be resolved, for instance as described by Shieh et al, J. Org.Chem. (1994) 59: 5463, for subsequent conversion to the correspondinggalanthamine structure. Alternatively, racemic bromonarwedine, or a saltderivative thereof, can be converted by dynamic entrainment orcrystallisation into an optically-enriched form thereof, for exampleusing a method of the general type described by Barton et al or by Shiehet al, discussed above. This can then be converted intooptically-enriched bromogalanthamine, for instance (-)-bromogalanthamineof formula (8), below, by reduction, for instance as described inInternational Application No. PCT/GB96/00843. The bromine atom can thenbe removed as described above, or replaced by different functionality.

Bromination of O'-dimethylgalanthamine has recently been described inEP-A-0649846 and EP-A-0648771, and this procedure affords theregioisomeric bromine derivative (9) which can be converted intogalanthamine analogues. The availability of bromonarwedine andbromogalanthamine by virtue of the present invention, therefore,provides a possible entry into other galanthamine analogues which wouldnot be accessible via semi-synthetic routes from galanthamine obtainedfrom natural sources.

The tertiary amine substrate for the phenolic coupling reaction can bemade by any of the known techniques. For instance, it can be made byreductive amination from 6-bromoisovanillin (from either isovanillin orveratraldehyde) and tyramine (or N-methyltyramine). Reference is made inthis respect to Kametani et al and Szewczyk et al, mentioned above, andto Bulavka et al, Khim. Farm. ZH. (1990) 24: 59.

While the above description concentrates on the (-)-enantiomers of therespective compounds, as these allow ready access to thetherapeutically-useful (-)-galanthamine, the chemistry is equallyapplicable to the (+)-enantiomers.

The present invention is now further illustrated by the followingExamples.

EXAMPLES Example 1 N,p-O'-Dimethylbromonorbelladine (6)

6-Bromoisovanillin (500 g) was suspended in MeOH (2.5 l) in a 5 l3-necked flask equipped with an overhead stirrer. Tyramine was added andthe resulting mixture was stirred at room temperature for 60 min andthen cooled to 0° C. NaBH₄ (67 g) was then added in approx 2.5 gportions keeping the temperature below 20° C., eventually forming asolution. After stirring for a further 60 min a precipitate had formed.HCHO (37% aq solution) (179 ml) was added in one portion at roomtemperature and stirred for 60 min during which time a solution formed.The solution was cooled to 0° C. and NaBH₄ (31.0 g) added, again inapprox 2.5 g portions keeping the temperature below 20° C. The mixturethen became quite thick as a white solid formed. MeOH (2.5 l) was addedto mobilise the mixture, which was then filtered to collect the whitesolid, washing with cold MeOH. Yield=780 g, 98%.

The N,p-O'-Dimethyl-6-bromonorbelladine (6) obtained (300 g) wasdissolved in IMS (3.0 l) and treated with charcoal (10 g). After hotfiltration the solution was allowed to cool yielding a white crystallinesolid. Recovery=231 g, 77%.

Example 2 Racemic Bromonarwedine (7)

Toluene (2.67 l) and water (333 ml) were placed in a 5 l jacketed vesseland the mixture was heated to 70° C. under nitrogen. K₂ CO₃ (33 g, 0.24mol) and K₃ Fe(CN)₆ were added and then the homogenizer was turned on.N,p-O'-Dimethyl-6-bromonorbelladine (6) (20 g, 52.6 mmol) was then addedin one portion. After 30 min. the homogenizer was turned off and themixture was filtered to remove a large amount of brown solid. The twolayers were separated and the toluene phase was washed with NaOH (2 M;500 ml). The product was then extracted into HCl (2 M, 500 ml). TBME(500 ml) and EtOAc (250 ml) were added and the aqueous layer wasneutralised. The organic phase was dried over Na₂ SO₄ and concentratedin vacuo to yield bromonarwedine (7) (6.27 g, 33%).

Example 3 Racemic Bromonarwedine (7)

N,p-O'-Dimethylbromonorbelladine (6) (as its formate salt) (1 g) wasadded to a stirred mixture of potassium ferricyanide (5.39 g) in 5%aqueous sodium hydrogen carbonate (50 ml) and toluene (100 ml) and themixture heated at 85° C. for 3 hours. The mixture was cooled andfiltered. The layers were separated and the organic phase evaporated togive racemic bromonarwedine (7) (0.113 g, 13%) substantially pure by NMRanalysis.

Example 4 Racemic Narwedine (1)

DMF (930 ml) was added to bromonarwedine (7) (187.3 g, 515 mmol), NaCO₂H (52.5 g, 772 mmol), PPh₃ (13.5 g, 51 mmol), Pd(OAc)₂ (5.78 g, 26 mmol)and NaCl (3.76 g, 103 mmol). The mixture was heated to 94° C., for 6hours at which point GC indicated complete reaction. The dark mixturewas diluted with CH₂ Cl₂ (2 l) and filtered. 2 M NaOH (2 l) was addedand the layers separated. The product was extracted from the CH₂ Cl₂using 2 M HCl (2 l). This was added to CH₂ Cl₂ (2 l) and the pH adjustedto 12 using 46-48% NaOH. The CH₂ Cl₂ was separated and concentrated toapprox 200 ml. MeOH (100 ml) was added and the remainder of the CH₂ Cl₂evaporated. The solid product formed (1) was collected by filtrationwashing with cold MeOH. Yield=122.2 g, 84%, purity>95% by HPLC.

The racemic narwedine obtained in Example 4 can then be converted tooptically-enriched galanthamine as described above. ##STR2##

What is claimed is:
 1. A process for preparing a compound having theformula (11) comprising oxidative cyclisation of a tertiary amine havingthe formula (12) ##STR3## wherein X¹ is a halogen or t-butyl, X² ishydrogen or a group as defined above for X¹, and R¹ is selected fromhydrogen and alkyl, aryl, alkaryl and aralkyl groups having up to 20carbon atoms, and R² and R³ are independently selected from hydrogen andalkyl, aryl, alkaryl, aralkyl and acyl groups having up to 20 carbonatoms.
 2. The process according to claim 1, wherein R¹ =R² =methyl, R³=hydrogen, X¹ =bromine and X² =hydrogen.
 3. The process according toclaim 1 or claim 2, which further comprises resolving the compound (11)to give compound (11) in optically-enriched form.
 4. A process forpreparing an optically-enriched compound having the formula (10),##STR4## in which the R and X groups are as defined in claim 1,comprising a process as defined in claim 3, followed by reduction of theproduct thereof.
 5. A process for preparing an optically-enrichedcompound having the formula (10), ##STR5## in which the R and X groupsare as defined in claim 1, comprising a process as defined in claim 1,followed by reduction of the product thereof to give a racemic compoundof formula (10), and subsequent resolution thereof.
 6. A process forpreparing an optically-enriched compound of formula (10) ##STR6## inwhich the R groups and X² are as defined in claim 1, and X¹ =hydrogen,comprising preparing an optically-enriched precursor compound of formula(10) by a process as defined in claim 4, and removing therefrom the X¹substituent.
 7. The process according to claim 3, for preparingoptically-enriched galanthamine, wherein in the precursor compound R¹=R² =methyl, X¹ =bromine and X² =hydrogen.
 8. A process for preparing anoptically-enriched compound of formula (10) ##STR7## in which the Rgroups and X² are as defined in claim 1 and X¹ =hydrogen, comprisingpreparing a compound of formula (11) as defined in claim 1, removingtherefrom the X¹ substituent, and reducing and resolving the productobtained as defined in claim
 4. 9. The process according to claim 2,wherein the compound (11) is resolved by entrainment or crystallisationof a salt thereof.
 10. The process according to claim 1, wherein R¹ isselected from the group consisting of hydrogen and alkyl, aryl andalkaryl groups having up to 20 carbon atoms.
 11. The process accordingto claim 1, wherein R¹ is selected from the group consisting of alkyl,aryl and alkaryl groups having up to 20 carbon atoms.
 12. A process forpreparing a compound of formula (11) ##STR8## in which the R groups andX² are as defined in claim 1 and X¹ is hydrogen, comprising reductivedebromination of a precursor compound of formula (11) in which R and X²are as defined in claim 1 and X¹ is bromine, to convert X¹ from bromineto hydrogen.
 13. The process according to claim 12, wherein in theprecursor compound both R¹ and R² are methyl and X² is hydrogen.
 14. Theprocess according to claim 12, which further comprises resolving theproduct obtained to form an optically-enriched form of compound (11).15. The process according to claim 13, which further comprises resolvingthe product obtained to form an optically-enriched form of compound(11).
 16. The process according to claim 12, wherein the precursorcompound of formula (11) is prepared by a process as defined in claim 1.